Pancreatic cancer is the fourth most common cause of cancer-related mortality for both men and women in the United States. Relatively little is known about the pathogenesis and epidemiology of this malignancy. Our general goals are: first, to examine prospectively hypotheses regarding the etiology of pancreatic cancer, and, second, to establish a unique database consisting of repeated dietary and lifestyle assessments over several decades, archived blood specimens, and archived tumor tissue. This resource will allow for the rapid examination of future hypotheses as they emerge. We will use the resources of three large cohort studies with prospectively collected blood specimens: the Nurses' Health Study (NHS), Health Professionals' Follow-up Study (HPFS), and Physicians' Health Study (PHS). Blood specimens will be analyzed using a matched, nested case-control design of projected cases through 2002 to evaluate hypotheses focusing on mechanisms of pancreatic cancer pathogenesis. First, we will examine whether an association between energy intake, obesity, greater adult height, sedentary lifestyle, or diabetes mellitus and pancreatic cancer is mediated through insulin-like growth factors and binding proteins. Second, we will examine whether biochemical indicators of methyl-group availability are associated with pancreatic cancer risk and whether the influence of folate is modified by methylene tetrahydrofolate reductase polymorphisms. Third, we will examine whether polymorphisms of genes responsible for detoxification and activation of aromatic/heterocyclic amines influence the risk of pancreatic cancer, and whether the associations of smoking and red meat intake with pancreatic cancer are influenced by these polymorphisms. Finally, we will examine the prevalence and spectrum of K-ras mutations, the prevalence of pl6 loss of heterozygosity and the level of p53, p21 and p27 expression among pancreatic cancers, and assess the influence of dietary and other factors on the prevalence of these molecular changes. These studies will enhance our understanding of pancreatic carcinogenesis and provide a scientific foundation for future preventive efforts. This is the first R01 submitted by the principal investigator following a K award from NCI.